The objective of this proposal is to chracterize the contribution of epidermal Langerhans cells (LC) to the induction of contact hypersensitivity (CH) and unresponsiveness in mice. The dominant hypothesis around which this work constellates states that Langerhans cells, unique within the epidermis, function as antigen presenting cells whereby they deliver to immunocompetent cells an unequivocal immunogenic signal; as a corollary hypothesis, when Langerhans cells fail, or are not adequately represented in cutaneous site of antigen application, an alternative signal escapes the skin, one which is perceived by the systemic immune system as a tolerogenic one. During the past several years, we have learned that (1) cutaneous surfaces depleted of normal appearing LC fail to sustain the induction of CH and fail to express Ia alloantigens; (2) epidermal LC are rapidly mobilized from a systemic precursor pool that reconstitutes deficiencies produced by experimental manipulation; (3) in vivo low dose ultraviolet B radiation (UVB) induces hapten specific T suppressor cells; (4) susceptibility of CH by local UVB is genetically determined by several loci and is a codominant phenotype; (5) unwitting oral ingestion of hapten following skin painting results in down regulation of CH; (6) hapten-derivatized skin grafted orthotopically induces CH with great efficiency and elicits effector cells genetically restricted by H-2 antigens of the graft. Most recently, we have produced highly purified Langerhans cells from mouse skin. During the next five years, we plan to take advantage of this technological advance to (a) prepare and characterize purified Langerhans cells, as well as other epidermal cell sub-populations by a variety of in vitro approaches; (b) describe immunologic properties of purified Langerhans cells both in vivo and in vitro; and (c) to analyze the role of resident Langerhans cells in the induction and regulation of contact hypersensitivity. Results of these studies will advance understanding of the immunopathogenesis of cutaneous immune disorders, including persisitent virus infections and development of neoplasms, especially in relation to sun-exposure.